Nucleophilic Dearomatization Strategy to Synthesize Disubstituted 3-Isoquinolinones under Transition Metal-Free Conditions

Abstract

Herein, a one-pot protocol for constructing the disubstituted isoquinolinone derivatives via the three-component reactions of 3-haloisoquinolines, alkyl halides, and indoles under transition-metal-free conditions is described. The reaction realized the trifunctionalization of isoquinoline via a dearomatization strategy, which displayed high chemical selectivity, excellent functional group tolerance, and a wide range of substrates, and is environmentally friendly. The three-component coupling involves the construction of new C−N, C�O, and C−C bonds in one step.

Recent Strategies in the Nucleophilic Dearomatization of Pyridines, Quinolines, and Isoquinolines

“…The three-component reaction of 3-haloisoquinolines 3 , alkyl halides 323 , and indoles 346 in the presence of AcONa as a base allowed the construction of disubstituted isoquinolinone derivatives 449 under metal-free conditions ( Scheme 216 ). 289 This transformation involved the trifunctionalization of the isoquinoline ring through a dearomatization strategy and it displayed high chemical selectivity and excellent functional group tolerance. Control experiments were performed in order to understand the mechanism of this transformation.…”

Application of Metal‐Free Dearomatization Reaction as a Sustainable Strategy to Direct Access Complex Cyclic Compounds

“…A series of isoquinolinone derivatives was obtained in moderate to good yields with high chemo‐selectivity and excellent functional group tolerance (Scheme 37). [45] The 3‐bromoisoquinoline 91 a reacts with benzyl bromide 92 a to give the N ‐alkylisoquinoline salt Q . This undergoes a nucleophilic attack by the hydroxide ion to genenrate the intermediate R with the release of the bromo anion.…”

Direct Synthesis of N‐Alkyl‐2‐Pyridones Using 2‐Halogenated Pyridines

“…In addition, Chen et al recently reported that 3-halogenated isoquinoline can be used in a one-pot approach to construct disubstituted isoquinolinone derivatives in aqueous phase. [11] Additionally, Helaja [12] prepared pyridone derivatives, utilising the directing O-benzyl groups in N-heterocycles under photogeneration conditions, while removing the protecting groups. Considering the significance of pyridones, developing novel, green synthetic strategies is highly desirable.…”

“…In addition, Chen et al. recently reported that 3‐halogenated isoquinoline can be used in a one‐pot approach to construct disubstituted isoquinolinone derivatives in aqueous phase [11] …”